Francisella tularensis is considered to be a Category A agent by the NIAID because of its extreme infectivity, ease of dissemination, and substantial capacity to cause illness and death. This Program Project brings together a diverse group of individuals with particular expertise in the fields of microbiology, cell biology, and mucosal immunology who are committed to continuing to explore in an integrated fashion, the pulmonary immune response to F. tularensis. Our group has made remarkable progress during the previous funding period as evidenced by, among other things, our multiple publications and the highly positive annual evaluations of our External Scientific Advisory Board. Of particular interest, we have recently demonstrated that mucosal vaccination with inactivated F. tularensis targeted to Fc receptors on antigen presenting cells or using an antioxidant mutant strain provides significant protection from pulmonary infection with the highly virulent SchuS4 strain. We now intend to build upon our achievements to: 1) Refine and further develop novel strategies for induction of anti-F. tularensis pulmonary immunity and determine the mechanisms responsible for protection. 2) Examine the coordinated intra- and extracellular recognition of F. tularensis. 3) Define the redox control of F. tularensis pathogenesis and its role in regulating immune protection. The overall goal of the Project continues to be development of vaccination platforms for effective protection at mucosal surfaces. A particular emphasis of the renewal application will be on complementary investigations that are focused on optimizing vaccine strategies to elicit protection against the highly virulent type A strain, SchuS4, in our fully approved animal BSL3.